DESCRIPTION: The goal of this small research grant proposal (R03) is to develop and evaluate a flexible, filamentous bionanomaterial for applications in cancer nanotechnology. A growing body of data suggests advantageous pharmacokinetic and tumor accumulation properties of long, elongated, filamentous nanomaterials compared to their spherical counterparts. Tailoring materials at the nanoscale to create such high aspect ratio materials remains challenging. Therefore, we have turned toward a bio-inspired approach: we will make use of nature's nanomaterials and adapt the filamentous plant virus grapevine virus A (GVA) as a novel carrier for delivery of therapeutics and contrast agents. The use of virus-based nanoparticles in medicine has been recognized and gene therapy vectors, vaccines, and oncolytic virotherapies are under development. The use of plant-derived materials, such as GVA, is considered safe from a human health perspective, because plant viruses are not pathogenic in mammals. Plant viruses can be engineered with therapeutic payloads, contrast agents, and targeting ligands to create tissue-specific drug delivery systems and imaging agents. Most (viral) nanoparticle systems under evaluation are spherical (i.e. icosahedral). It is becoming increasingly clear that filamentous (bio)nanomaterials are of broad biomedical interest. GVA presents a novel biomaterial; its highly flexible structure may offer advantages over hard or low aspect ratio materials currently in the development pipeline. GVA is a highly flexible, 800 x 12 nm filament formed by approximately 4,200 identical copies of a coat protein. In addition to its soft and flexible structure, GVA offers a high aspect ratio and large surface area allowing to deliver high payloads of drugs or imaging agents. The goals of this proposal are to (1) establish large-scale production of GVA and develop bioconjugate chemistry protocols enabling functionalization of the nanofilaments with imaging moieties, stealth and/or camouflage, and targeting ligands, and (2) to gain an understanding of the pharmacokinetics, immunogenicity, and biodistribution properties, specifically its tumor accumulation properties. We hypothesize that GVA will show favorable in vivo behavior and enhanced partitioning to tumors (tumor uptake>>liver uptake) based on its biophysical properties. Data gained will lay the foundation for the further development of GVA for nanomedical applications. The PI has a track record of developing virus-based materials for medical applications and is thus uniquely suited to develop and oversee the proposed research. The data gained from the proposed study is a critical stepping-stone for the GVA technology development and will lay a foundation for application GVA-based materials in medicine. We envision broad applications of GVA, which include its application as a gene, drug, or contrast agent delivery vehicle. GVA could find applications in cancer medicine, cardiovascular disease as well as infectious disease. This is a self-contained research project focused on the development of a new technology; the proposal is thus well aligned with the R03 mechanism.